CHICAGO — The two most popular medications for erectile dysfunction (ED) may confer substantial cardiovascular benefits for men with ED and concurrent heart disease, according to an analysis of a health research database.

Both sildenafil and tadalafil significantly reduced the likelihood of progression to heart failure, myocardial infarction (MI), and death after 5 years as compared with men taking neither drug. Tadalafil had a more pronounced effect on all three clinical events than did sildenafil, reported Albert Ha, MD, of the Columbia University Irving Medical Center in New York City, during the American Urological Association annual meeting.

“PDE5 [phosphodiesterase 5] inhibitors are useful drugs that really are active in multiple ways to benefit patients with both ED and cardiac issues,” said Ha. “There are differences in the individual drugs’ effectiveness. We speculate that these differences may be due to pharmacokinetic differences and cross-reactivity with other PDE enzymes.”

Ha acknowledged the database’s lack of granularity for clinically relevant variables and drug dosing but said the findings warrant additional study.

During a discussion that followed the presentation, several members of the audience lauded the study and the data for identifying benefits with potentially widespread application. The discussion also brought attention to a potential limitation that Ha did not mention.

“One of the distinct differences between those who have PDE5 inhibitor prescriptions … [is that they are] more interested in or want to have physical activity than the people who did not have prescriptions, presumably,” said unidentified speaker. “Is there a way to look at this cohort and identify the patients who are similarly interested in physical activity that you can match or pair?”

Ha said ongoing analyses of the data are focused on refining the cohorts with and without PDE5 inhibitor prescriptions in an effort to capture variables associated with cardiovascular health, including physical activity.

A second study reported during the session provided a measure of reassurance about PDE5 inhibitor safety. Some evidence had linked the drug class to ocular adverse events, but a review of a large insurance database showed no consistent association between PDE5 inhibitor use and ocular events, reported Federico Belladelli, MD, of Universitá Vita-Salute San Raffaele in Milan.

ED and Heart Disease

An estimated 10 million men in the U.S. have ED, and sildenafil and tadalafil are the first-line treatments for many of them, said Ha. ED has a recognized association with heart disease, as both conditions often involve circulatory dysfunction.

“Contrary to what most people believe, PDE5 inhibitors also have been shown to alter endothelial function and improve myocardial perfusion,” he said. “We know there is data out there suggesting that PDE5 inhibitors lead to cardiac benefits, including improved cardiac function and possibly microvascular improvement.”

Ha and colleagues undertook an investigation of the association between the PDE5 inhibitors sildenafil and tadalafil with heart failure and other major adverse cardiac events in men with concurrent coronary artery disease (CAD) and ED. Using data from the TriNetX Research Network, they identified men with diagnoses of heart disease and ED during 2011 to 2016.

After propensity matching, data analysis included 6,751 men with prescriptions for tadalafil, 12,214 with sildenafil prescriptions, and 22,321 men with no PDE5 inhibitor prescriptions. The primary outcome was the 5-year incidence of heart failure, MI, and mortality.

Comparing outcomes for men with tadalafil versus no PDE5 inhibitor treatment, investigators found that tadalafil reduced the risk of heart failure at 5 years by 33%, MI by 25%, and overall mortality by 41%. The comparison of sildenafil versus no PDE5-inhibitor treatment yielded reductions of 22% for heart failure, 12% for MI, and 35% for overall mortality. All comparisons for both PDE5 inhibitors achieved statistical significance.

In a comparison of men prescribed tadalafil versus those prescribed sildenafil, Ha and colleagues found that tadalafil significantly reduced the 5-year risk of heart failure by 15%, MI by 14%, and overall mortality by 15%.

Ocular Effects of PDE5 Inhibitors

Belladelli reported findings from an analysis that explored the association between PDE5 inhibitors and ocular adverse events (AEs), specifically serous retinal detachment (SRD), retinal vascular occlusion (RVO), and ischemic optic neuropathy (ION). He noted a recognized overlap of risk factors for major ocular events and ED.

Data for the study came from the IBM MarketScan Commercial and Medicare Supplemental Databases for the years 2007 to 2021. Investigators adjusted for geographic region, age, obesity, diabetes, hyperlipidemia, smoking, hypertension, CAD, and sleep apnea. They performed separate analyses for men with a diagnosis of benign prostatic hyperplasia (BPH).

The data showed that 1,938,262 men had an ED diagnosis during the study period and 615,838 had prescriptions for a PDE5 inhibitor. Additionally, 2,175,439 men had a BPH diagnoses, 175,725 of whom had PDE5 inhibitor prescriptions.

Among men with an ED diagnosis and PDE5 inhibitor prescription, an adjusted analysis yielded HRs of 1.02 for SRD, 1.04 for RVO, and 0.97 for ION, none of which achieved statistical significance. For the combination of SRD, RVO, and ION, PDE5-inhibitor use was not significantly associated (HR 1.001).

For the group of men with BPH and PDE5-inhibitor prescriptions, a statistically significant association was observed for RVO (HR 1.14, 95% CI 1.06-1.23). Belladelli noted that the patients received other treatments, including 5-alpha reductase inhibitors and surgery, both of which had significant associations with RVO.

“We did not observe any consistent association between PDE5 inhibitor use and any ocular adverse events,” he said. “However, patients who required more intense treatment for ED and BPH had a higher risk of ocular events, implying shared risk factors as an etiology.”

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